There has been relatively little focus on the prevention of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS). Recently, intensive insulin therapy (NT) have been shown to decrease morbidity and/or mortality in critically ill patients with prolonged intensive care unit (ICU) stays, but the utility of NT to protect against early critical illness events such as ALI/ARDS is unknown. The broad objective of this proposal is to assess the potential of early IIT to prevent ALI/ARDS in at-risk populations. In Aim #1, the association between early insulin therapy and development of ARDS will be examined in a retrospective nested case control study based on the Molecular Epidemiology of ARDS, a large prospective study of patients at risk for ARDS. However, any intervention to prevent ALI/ARDS must occur early, preferably prior to ICU admission, since 38% of ARDS patients fulfill ARDS criteria on the day of ICU admission. Thus in Aim #2, in a randomized control trial, the potential of early IIT initiated in the Emergency Department (ED) to reduce lung injury and modulate mediators implicated in sepsis-related ALI/ARDS will be examined. The method of propensity score analyses and multivariate logistic regression models will be used to account for potential confounders in Aim #1. In Aim #2, lung injury as measured by the Murray Lung Injury Score (LIS) will be recorded serially in the first week of sepsis. In addition, blood samples will be collected from patients with severe sepsis on admission to the ED and on Day 1 and 3 of the study and plasma levels of free fatty acids, tumor necrosis factor-a, interleukin-6 and Von Willebrand Factor antigen will be determined by liquid and gas chromatography and by ELISA. Analyses of covariance will be used to compare the change in LIS and plasma levels over time between patients randomized to receive early IIT in the ED versus the standard ICU group who receive IIT 48 hours after ICU admission. This proposal has significant health relatedness to the NHLBI's mission and relevance to public health. ALI/ARDS is a devastating form of lung injury with significant mortality, morbidity, and health care costs. Any intervention that can decrease the incidence of ALI/ARDS will have a significant epidemiologic impact in lives saved and morbidity averted.